Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. HIV-1 resistance to nucleoside RT inhibitors such as AZT can arise through mutations in the coding region of RT. Recently a series of thioterazolyl acetanilides were reported as potent inhibitors of HIV-1 wild type and double mutant K103N/Y181C reverse transcriptase. In the present study 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoFMA) were performed on 28 thiotetrazole alkynylacetanilides. CoMFA was performed using sibyl software 6.7v. The molecules were divided into training set and test set. The developed model based on training set containing 20 molecules gave Q2 value of 0.587 and non cross validation R2 value of 0.961 and standard error of estimate 0.098 for CoMFA. The steric and electrostatic contributions are 42.7% and 57.3% The cross validation on test set gave R2 value of 0.74. The CoMFA model provided the most significant correlation of steric and electrostatic fields with biological activities. The information rendered by 3D QSAR model may afford valuable clues to optimize the lead and design new potential inhibitors